This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In contrast to HIV-1 infection of humans and SIV infection of Rhesus macaques (RMs), which are associated with AIDS, natural lentiviral infections of African primates, such infection of Sooty mangabeys (SM), are typically non-pathogenic. The mechanisms underlying this nonpathogenic phenotype remain largely unknown. However, we have previously shown that nonpathogenic SIV infection occurs in absence of chronic, generalized immune activation and proposed that the lack of IA protects SIV-infected SMs from disease progression. In the past year we made progress in our proposed comparative studies of innate and adaptive immunity in SMs and RMs. First, we completed the analysis of an in vivo experiment of comparative SIV infection of SMs and RMs in which, using microarray analysis, we were able to define the molecular signature associated with acute and chronic SIV infection in these two species, and thus identify new potential targets for interventions aimed at modifying the level of immune activation. Second, we initiated an in vivo experiment consisting in the administration of a type I IFN agonist to naturally SIV-infected SMs during chronic phase of infection. This study is designed to test the hypotheses that the benign, non-pathogenic nature of SIV infection in SMs with low immune activation in the chronic phase is related to the absence of continuous production of type I IFNs and ISG up-regulation, and that experimental administration of IFN-a agonists will recapitulate the state of chronic immune activation observed in pathogenic HIV and SIV infections of humans and RMs, respectively. Six naturally SIV infected SMs and two uninfected controls were treated with IFNs intravenously for 15 weeks. This experiment was only recently completed and the obtained results have not been fully analyzed.